Cancer Cell
Volume 39, Issue 2, 8 February 2021, Pages 209-224.e11
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Article
MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

https://doi.org/10.1016/j.ccell.2020.12.010Get rights and content
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Highlights

  • Development of MAT2A inhibitors (MAT2Ai) AGI-24512 and AG-270 with improved potency

  • AGI-24152 and AG-270 reduce proliferation of cancer cells and tumors that lack MTAP

  • MAT2Ai reduce PRMT5 activity affecting mRNA splicing and inducing DNA damage

  • Antiproliferative effects of AG-270 are synergistic with taxanes in vitro and in vivo

Summary

The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP−/− cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.

Keywords

MAT2A
PRMT5
splicing
detained introns
DNA damage
Fanconi anemia complex
R loops
taxanes
synergy

Cited by (0)

11

Present address: Rheos Medicines, Cambridge, MA 02142, USA

12

Present address: Exploratory Biology, Novartis Institutes for Biomedical Research, Cambridge, MA 02319, USA

13

Present address: Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA 02319, USA

14

Present address: Chemistry, Takeda Pharmaceutical Co., Ltd., Lexington, MA 02421, USA

15

Present address: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA

16

These authors contributed equally

17

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